A family of lethal exotoxins defined by cell entry via the Attractin receptor

Although bacterial genomes encode numerous potential toxins, it is unclear how evolution drives the specificity of these important virulence factors. Using an insect CRISPR screen, we identified the transmembrane protein Attractin (ATRN) as the receptor for Nigritoxin (Ntx), a Vibrio toxin that causes seasonal shrimp pandemics. We found that Ntx’s effector “warhead” inhibits translation via a previously uncharacterized mechanism. Moreover, we show that two related toxins require ATRN for entry but possess unrelated effector domains. One has a Rho-GTPase AMPylation function and the other an actin-targeting/proteolysis function. Our findings reveal the mechanism of Ntx entry and toxicity and show that the ATRN-targeting domain can deliver disparate effector domains, strongly indicating that this class of exotoxins can evolve as modular proteins using a common entry domain.Competing Interest StatementThe authors have declared no competing interest.NIH, 5P41GM132087, 3R01AI170835, R01AI018045Quadrangle Fund for Advancing and Seeding Translational Research at Harvard Medical SchoolHoward Hughes Medical Institute, https://ror.org/006w34k90